Abstract：
Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4+ TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.
摘要：
具有受损的效应子功能和PD-1表达的人CD8肿瘤浸润淋巴细胞(TIL)被归类为耗尽。然而,TIL中报道的耗竭样特征可能源于其激活,而不是T细胞耗竭本身的结果.使用CRISPR-Cas9和慢病毒在非癌性供体的CD8T细胞中的过表达，我们显示T细胞受体（TCR）诱导的转录因子干扰素调节因子4（IRF4）促进细胞增殖和PD-1表达，并阻碍效应子功能和核因子κB（NF-κB）调节基因的表达。尽管具有干扰素γ（IFNγ）产生受损的CD8TIL表现出激活标记IRF4和CD137以及与高迁移率组盒（TOX）和PD-1相关的耗竭标记胸腺细胞选择，但COVID-19患者的活化T细胞并未表现出升高的TOX和PD-1水平。这些结果证实IRF4+TIL耗尽而不是单独活化。我们的研究表明,然而,PD-1表达，IFNγ产量低，T细胞活化后，TIL中的活性循环都受到IRF4上调的影响。
